AU2015291363A1

AU2015291363A1 - Combination of valerian root extract and lavender oil for use in the treatment of sleep disorders

Info

Publication number: AU2015291363A1
Application number: AU2015291363A
Authority: AU
Inventors: Wilfried Dimpfel; Michael Noldner
Original assignee: Dr Willmar Schwabe GmbH and Co KG
Current assignee: Dr Willmar Schwabe GmbH and Co KG
Priority date: 2014-07-14
Filing date: 2015-06-10
Publication date: 2017-01-12
Anticipated expiration: 2035-06-10
Also published as: PT2974733T; ES2597784T3; HUE031669T2; AU2015291363B2; MX2017000472A; WO2016008650A1; US20170296612A1; TW201613628A; CA2953190C; JP2017521446A; EP2974733A1; TWI654987B; JP6474114B2; MY177827A; RU2672876C2; EP2974733B1; CA2953190A1; CN106573029A; US10357530B2; CN106573029B

Abstract

The present invention relates to the use of a combination of valerian root extract and lavender oil for the treatment of sleep disorders, and to a combination drug comprising valerian root extract and lavender oil.

Description

26313WO WE/sg

Combination of Valerian Root Extract and Lavender Oil for Use in the 5 Treatment of Sleep Disorders

The present invention relates to a combination of valerian root extract and lav-10 ender oil for treating sleep disorders as well as to a combination preparation comprising valerian root extract and lavender oil.

The present invention relates to the use of a combination of lavender oil and valerian root extract as a highly potent sleep-inducing agent. The combination leads to a synergistic overadditive activity with respect to the induction and 15 soundness of sleep.

Lavender oil is manufactured for different purposes and is used e.g. in aroma therapy. In particular, it is traditionally said to have a calmative effect. A special preparation for oral administration has been approved for several years as a medical agent in Germany for treating conditions of uneasiness and anxious 20 depressive mood (Lasea® of Dr. Willmar Schwabe GmbH & Co. KG). Valerian root extract is traditionally used in case of nervous related sleep disorders and also exists as a medicament (e.g. “Baldiparan® Stark fiir die Nacht" of Pfizer Consumer Healthcare GmbH).

Although there are reports about possible biological or pharmacological effects 25 of lavender oil for treating sleep disorders, no reliable clinical studies exist for this application. A combination with valerian root extract for improving sleep has not yet been described. Therefore, the finding that lavender oil is capable, de- -2- spite the very weak effect on its own, to significantly enhance the effect of valerian root extract, or to multiply the same, respectively, is all the more surprising. Examinations in Tele-Stereo-EEG of rats within the frame of experiments of a different object revealed hints to the existence of such an overadditive, multiply-5 ing effect.

The presently common medical agents for treating sleep disorders show a broad spectrum of side effects (addiction and development of tolerance for benzodiazepines).

Thus, there is a considerable need for improved treatment possibilities for sleep 10 disorders, either as medical agent or as food, with good efficiency at a low rate of side effects. This low rate of side effects is expected to be more likely in the administration of a natural compound or a combination of natural compounds.

This problem has surprisingly been solved by using lavender oil in combination with valerian root extract. is The invention relates to the combination of valerian root extract and lavender oil for use in the treatment of sleep disorders. The combination may optionally comprise further natural compounds from plants or extracts, however, it preferably does not comprise any further extracts from plants and/or oils from plants and/or other pharmaceutically active agents (drugs). The combination compris-2o ing valerian root extract and lavender oil for use in the treatment or prophylaxis of sleep disorders may be a dosage form, i.e. in the form of a medicament or food and may be present as two separate dosage forms, i.e. in the form of two separate medicaments or food, each of which contain the valerian root extract or the lavender oil, respectively. For the case that valerian root extract and lav-25 ender oil are present in separate dosage forms, e.g. in the form of a medicament or food, these can be administered simultaneously or subsequently in any order, i.e. valerian root extract first, followed by lavender oil, or lavender oil first and subsequently valerian root extract. The time sequence of administration should not be longer than an hour, preferably no longer than 30 minutes and -3- particularly preferably no longer than 10 minutes. Preferably, also in case of separate administration, the valerian root extract and the lavender oil are administered simultaneously or almost simultaneously, i.e. within a few minutes (up to 10 minutes). 5 The invention also relates to a combination preparation consisting of a valerian root extract and lavender oil and optionally auxiliary agents which are pharmaceutically acceptable or acceptable under food law in a dosage form, i.e. in a medicament or food.

The following explanations refer both to the invention use of the combination io comprising valerian root extract and lavender oil, and also to the combination preparation according to the invention comprising valerian root extract and lavender oil and optionally pharmaceutically acceptable auxiliaries, or auxiliaries acceptable under food law in a dosage form, i.e. in a medicament or food, respectively. is In vivo trials using rats show results confirming the superiority of the combination of lavender oil with an extract of valerian root. The overadditive and synergistic effect, which has been surprisingly found, has been document in vivo using rats, and was subsequently verified for the case of individual patients having sleep disorders. 20 Brief description of the drawings

Fig. 1 Time course of theta waves over 5 hours after administration of the individual components (80 mg/kg valerian root extract; 80 mg/kg lavender oil) in comparison to the combination of valerian root extract and lavender oil (80 mg/kg + 80 mg/kg) for the case of rats. The y-axis shows the power density 25 in % of the change from the pre-value of 45 minutes before administration. It is to be noted that both components, when administered alone within the first hour, do not have any effect on this frequency, however, in case of a combination they are already efficient. The synergistic effect is overadditive. -4-

Fig. 2 Time course of alpha 2 waves during 5 hours after administration of the individual components (80 mg/kg of valerian root extract; 80 mg/kg of lavender oil) in comparison to the combination of valerian root extract and lavender oil (80 mg/kg + 80 mg/kg) for the case of rats. The y-axis shows the power density 5 in % of the change from the pre-value of 45 minutes before administration. As already described for the theta waves, an overadditive effect is developed starting from the first hour after oral administration.

Fig. 3 Time course of beta 1 waves during 5 hours after administration of the individual components (80 mg/kg of valerian root extract; 80 mg/kg of lavender io oil) in comparison to the combination of valerian root extract and lavender oil (80 mg/kg + 80 mg/kg) in the rat model. The y-axis shows the power density in % of the change from the pre-value of 45 minutes before administration. As already described for the theta and a!pha2 waves, an overadditive effect is developed starting from the first hour after oral administration. is Fig. 4 Time course of electrical power of all frequency ranges during 5 hours after administration of vehicle (methyl cellulose) in four areas of the brain: frontal cortex, hippocampus, striatum and formatio reticularis. The six frequency ranges of delta (6), theta (Θ), alphal (a1), alpha2 (a2), betal (β1) and beta2 (β2) are documented on the x-axis. 20 Fig. 5 Time course of electrical power of all frequency ranges during 5 hours after administration of 80 mg/kg of valerian root extract alone in four areas of the brain: frontal cortex, hippocampus, striatum and formation reticularis. The six frequency ranges of delta (δ), theta (Θ), alphal (a1), a!pha2 (a2), betal (β1) and beta2 (β2) are documented on the x-axis. The statistical significance in 25 comparison to the control (vehicle) is documented by asterisks: *“p<0.05; **=p<0.01.

Fig. 6 Time course of electrical power of all frequency ranges during 5 hours after administration of 80 mg/kg of lavender oil alone in four areas of the brain: frontal cortex, hippocampus, striatum and formation reticularis. The six frequen- -5- cy ranges of delta (δ), theta (Θ), alphal (a1), alpha2 (a2), betal (β1) and beta2 (β2) are documented on the x-axis. The statistical significance in comparison to the control (vehicle) is documented by asterisks: *=p<0.05; **=p<0.01.

Fig. 7 Time course of electrical power of all frequency ranges during 5 hours 5 after administration of the combination of 80 mg/kg of valerian root extract and 80 mg/kg lavender oil alone in four areas of the brain: frontal cortex, hippocampus, striatum and formation reticularis. The six frequency ranges of delta (δ), theta (Θ), alphal (a1), alpha2 (a2), betal (β1) and beta2 (β2) are shown on the x-axis. The statistical significance in comparison to the control (vehicle) is doc-io umented by asterisks: *=p<0.05; **=p<0.01; ***=p<0.001.

In examination of EEG frequency changes of the rats, it was surprisingly found in comparison to the sole administration of valerian root extract that a significantly stronger increase in spectral performance was achieved after combination with lavender oil, which is useful in the treatment of sleep disorders, since is the increase in those frequencies correlates to the soundness of sleep. The sole administration of a vehicle did not cause any changes in electrical power (Fig. 4).

Fig. 1 shows the time-dependent changes in theta EEG frequencies after oral administration of various dosages of lavender oil, or of valerian root extract 20 alone, and as a combination. In earlier experiments, it could be shown that particularly the theta and betal waves of the EEG represent the soundness of sleep (Dimpfel W, Hofmann H-C Mehrdimensionale Dokumentation des Schlafes auf der Grundiage der Frequenzanalyse. In: Mayer G (ed.). Jahrbuch Schlafmedizin Deutschland 1994: MMV Verlag, Munich). Although lavender oil, 25 when administered alone, merely results in an increase of the theta frequencies, it can be seen that the small effect of valerian root extract is outperformed despite the high dosage, and, thus, a greater soundness of sleep is achieved. The alpha2 frequencies also change in an analogous manner (Fig. 2). The same applies to the betal frequency which is important for the soundness of sleep. As -6- shown in Fig. 3, the effect of the combination outperforms the effect of both individual preparations significantly, where both valerian root extract and lavender oil alone merely show any effect. This synergistic effect could be confirmed for the case of individual patients having sleep disorders. These results demon-5 strate that the combination of valerian root extract and lavender oil leads to a highly potent natural medicine for treatment of sleep disorders with low side effects.

According to a preferred embodiment, the sleep disorders are selected from disorders of initiating and maintaining sleep (G47.0 according to ICD-10), circa-io dian rhythm sleep disorders (G47.2 according to ICD-10), sleep apnoea (G47.3 according to ICD-10), nonorganic insomnia (F 51.0 according to ICD-10), non-organic disorders of the circadian rhythm (F51.2 according to ICD-10), sleepwalking (somnambulism, F51.3 according to ICD-10), pavor nocturnus (F51.4 according to ICD-10), as well as nightmares (anxiety dreams, F51.5 according 15 to ICD-10).

According to the invention, lavender oil is used in combination with valerian root extract. The two components, lavender oil and valerian root extract, can be applied as a mixture in a dosage form (combination preparation) or as separate dosage forms. In both cases, additional pharmaceutically acceptable auxiliary 20 agents and/or agents acceptable under food law, respectively, may be contained. According to a further preferred embodiment, no further plant extracts and/or oils from plants and/or other pharmaceutically active agents (drugs) are contained in the combination.

The valerian root extract which is contained in the combination used according 25 to the invention is preferably prepared from dried roots of Valeriana officinalis. The preparation of the extract is preferably performed using aqueous ethanol or aqueous methanol as extraction solvent, where particularly ethanol and water in a volume ratio of 30/70 to 90/10, or methanol and water in a volume ratio of 40/60 to 55/45 are employed. -7-

According to a preferred embodiment, as the valerian root extract, a valerian root dry extract is used. (According to the European pharmacopeia, a dry extract has a loss on drying, or a water content, respectively, of less than 5%). The dry valerian root extract preferably comprises at least 0.25 wt.-% of ses-5 quiterpene acids (total of valerenic acid, hydroxyvalerenic acid and ace-toxyvalerenic acid, calculated as valerenic acid) and thus complies with the requirements of the European Pharmacopeia, Edition 8.0. According to a further preferred embodiment, the weight ratio of valerenic acid or acetoxyvalerenic acid is at least 2/1. io The lavender oil used in the above combination according to the invention is preferably prepared by steam distillation of flowers of Lavandula officinalis and is optionally purified by a further distillation, in accordance with the European Pharmacopeia Monograph, Edition 8.0, “Lavender Oil”. According to a preferred embodiment, the lavender oil comprises 20.0 wt.-% to 45.0 wt.-% of linalool and is 25.0 wt.-% to 47.0 wt.-% of linalyl acetate as well as at most 1.0 wt,-% of limo-nene, at most 2.5 wt-% of 1,8-cineol, 0.1 wt.-% to 5.0 wt.-% of 3-octanone, at most 1.2 wt.~% of camphor, 0.1 wt.-% to 8.0 wt.-% of terpinen-4-ol, at least 0.2 wt.-% of lavandulyl acetate, at least 0.1 wt.-% of lavandulol and at most 2.0 wt-% of alpha-terpineol and thus complies with the requirements of the European 2o Pharmacopeia, Edition 8.0.

According to the invention, lavender oil and valerian root extract can also be used in the form of highly purified preparations. The production of such preparations is known per se.

The medicament or food, respectively, i.e. the combination preparations, and 25 the separate dosage forms, which solely comprise lavender oil or valerian root extracts as the active components, respectively, are preferably administered orally. However, an administration by means of other pathways, such as rectal-ly, is possible. -8-

For administration, the drug or food which contains the combination of valerian root extract and lavender oil, or separately the valerian root extract and the lavender oil, respectively, can be formulated e.g. as a solid preparation (e.g. a tablet, capsule, dragee, pellet, granule, suppository) or liquid preparation (solution, 5 emulsion, suspension) where the active agent may be optionally combined with pharmaceutically acceptable auxiliaries or carriers.

In case the medicament or food, respectively, is present in a form which can be administered orally, then it preferably comprises a combination of valerian root extract and lavender oil in a weight ratio of 12.5:1 to 1:2.5, preferably 7:1 to 1:1. io Other mixing ratios are possible.

The medicament or food comprising lavender oil and valerian root extract as active components is prepared according to common methods and is administered in a pharmaceutically suitable form.

Beside the active drugs (active components) the solid preparations may contain is additives which are common in pharmacy and food technology. For example, common excipients are sugars (lactose, sucrose), sugar alcohols (mannitol, sorbitol, maltitoi, xylitoi, tsomaltol), starch or cellulose. Furthermore, other technologically required additives may be present, such as thickeners (gelatine, gum arabic, cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrol-2o idone), flow agents (highly dispersed silica, precipitated silica), disintegrating agents (croscarmellose, crospovidone), lubricating agents (magnesium stearate, calcium stearate, stearic acid, glyceryl behenate).

For improvement of intake and to cover any unpleasant flavour or smell, the solid forms (e.g. tablets) can be coated with common coating agents. For coat-25 ing, solutions of sugars or sugar alcohols can be used, i.e. dragees may be prepared. Alternatively, the solid forms can be provided with a polymer coating film, i.e. coated tablets can be prepared. These films usually consist of a coating polymer (e.g. hydroxypropyl methyl cellulose), softening agent (e.g. polyethylene glycol, glycerol, triethyl citrate, glyceroltriacetate), anti-sticking agent (e.g. -9- talcum, glycerol monostearate), anti-foaming agent (polydimethylsiloxane) and organic or inorganic colouring pigments (e.g. iron oxide, titanium dioxide, carmine).

In order to prevent an excessively fast disintegration of the solid dosage form 5 after intake in connection with a sense of unpleasant flavour or odour and following eructation, the solid dosage form can be provided with a coating which prevents disintegration in the stomach and effects release of the active agents in the intestine. For this purpose, coating polymers which are insoluble in the gastric juice, however soluble in the chyle, such as poly(methacrylic acid-co-10 ethylacrylate) or shellac are commonly used. A further preferred embodiment of the invention is the use of capsules as dosage form. Capsules provide the advantage that quite different compounds in solid or liquid form can be included in various amounts. For the case of the aforementioned capsules, there are two different embodiments, i.e. hard cap-15 sules consisting of two parts which are plugged together after filling, and soft capsules which are formed, filled and sealed in one step. In the latter case, the joint of the capsule is provided with a banderole after sealing in order to prevent leakage of the product. Soft capsules are usually made of gelatine or a mixture of carrageenan and modified starch and are filled with liquid products in the 20 form of solutions, emulsions or suspensions.

The liquid dispersions for oral administration can e.g. be syrups, emulsions or suspensions.

Besides water, the syrup may contain sugars (e.g. sucrose), sugar alcohols (e.g. sorbitol, mannitol, xylitol) as solvents, solvent aids (glycerol, propylene giy-25 col), as well as other additives (preservatives, acidifying agents, flavouring agents).

The dosage regimen of the medicament or food, respectively, is preferably in the range of 80 to 600 mg, particularly preferably 250 to 500 mg of valerian root -10- extract, in combination with 40 to 200 mg, particularly preferably 40 to 80 mg of lavender oil per single dose. The single dose may be administered e.g. one to three times, preferably one to two times daily. A preferable combination comprises 250 to 500 mg of dry valerian root extract and 40 to 80 mg of lavender oil 5 per single dose. A particularly preferable combination comprises 500 mg of dry valerian root extract and 80 mg of lavender oil, or 250 mg of dry valerian root extract and 40 mg of lavender oil, respectively.

In case of using further extracts, the amounts used have to be adapted correspondingly in the manner known to the skilled person. io The combination preparations according to the invention can be used both as medicament and as food. In this respect, the term food particularly includes dietetic food, food supplements as well as medical food and dietary supplements.

Test methods 1. Pentobarbital-induced sleep time of mouse 15 In order to examine the influence of lavender oil (prepared according to Example 2), valerian root extract (prepared according to Example 1), and the combination of both substances, respectively, on the sleep of mice, the model of pentobarbital-induced sleep time by was chosen. In this respect, the animals are treated with the testing substances and, subsequently, pentobarbital is applied 20 in order to measure whether the induced sleep time changes. Sedating test agents extend the sleep time induced by pentobarbital.

Changes in sleep time after administration of agarose gel (control) and of lavender oil, valerian root extract, or lavender oil and valerian root extract in combination, respectively, was determined. 25 32 male NMRI mice from the breeder Janvier, LaGenest, France were used for the test after acclimatisation time of at least one week. The experiment itself was started with orally treating the mice with the control or test substances (lav- -11- ender oil or valerian root extract, or the combination of both). One hour later, all test animals received an interperitoneal application of 45 mg/kg pentobarbital to induce sleep. Subsequently, the mice were observed in regular intervals and upon recognising sedation of the animals, the positional reflex was tested (the 5 animals were placed supine, and in case they remain lying this was defined as sleep/sedation) and the time of falling asleep was recorded. If the sedation decreases and the animals wake up, they turn into abdominal position, and this time point which was defined as time of wake-up was also documented. The time period from falling asleep until wake-up is the sleep time. Two hours after io individual start of sleep, the experiment was terminated. Animals which were asleep for a longer time, were defined as having a sleep time of 2 hours.

The sole administration of valerian root extract or lavender oil does not lead to changes in sleep time induced by pentobarbital. However, administration of valerian root extract and lavender oil leads to a highly significant extension of 15 sleep time (see Table 1).

Table 1: Sleep time induced by pentobarbital after administration of agarose gel (control) and of lavender oil, valerian root extract or lavender oil and valerian root extract in combination, respectively

Substance Dosage mg/kg Sleep time (minutes) Control 46.9 ± 21 Valerian root extract 80 38.4 + 27 Lavender oil 80 57.4 ± 23 Valerian root extract + lavender oil 80 + 80 90.8 ± 32 * # p < 0,01 T-Test -12- 2. Tele-Stereo-EEG of rats

The changes in EEG frequencies after administration of methyl cellulose (control), or of lavender oil (prepared according to Example 2), valerian root extract (prepared according to Example 2) or lavender oil and valerian root extract in 5 combination, respectively, were determined.

Examinations were performed in analogy to the method described by W. Dimpfel (Dimpfel W: Preclinical data base of pharmaco-specific rat EEG fingerprints (Tele-Stereo-EEG). Eur J Med Res (2003) 8:199-207) as follows:

Concentric electrodes together with a microplug on a common basis plate were io implanted into eight male adult Fischer-344 rats (day-night converted) at the age of 6 months. The plug served to receive a 4-channel transmitter for telemetric transmission of the field potentials derived from frontal cortex, hippocampus, striatum and formation reticularis. The signals were subjected to fast Fourier transformation on a computer system (software: “EEG-Analyse”, operating sys-15 tern: OS Science, laboratory computer “LabTeam” of MediSyst, Linden, Germany) in real time and the performance density spectra were averaged over 60 minutes each. The subdivision of the spectra in 6 different frequency ranges allowed the recording of pharmaco-specific changes with respect to the preceding values within those frequency bands measured before administration, 20 45 minutes after start of the measurements, the preparations were administered orally (stored value). The measurement was resumed 5 minutes later and analysed continuously at least over the next 5 hours and subsumed in periods of 60 minutes. The test substances were administered in different combinations. The experimental series was started with administration of methyl cellulose (control), 25 which did not lead to any noticeable change.

The statistical comparison of the experiments relating to the results measured after administration of methyl cellulose was made according to Wilcoxon, Mann -13- and Whitney on the basis of the changes within the individual frequency bands in ail brain regions as the variables.

Administration of methyl cellulose hardly effected any changes in electrical power (pV2) in comparison to the phase pre-values (Fig. 4). The sole admin-5 istration of valerian root extract or lavender oil effected very weak, barely measurable changes of the spectral performance, which were only recognisable starting from the second hour after administration (see Figs. 1, 2, 3 as well as 5 and 6).

In contrast, administration of lavender oil in combination with valerian root ex-10 tract led to very early and stable changes in performance density already in the first hour after administration, in particular in the cortex, but also during the third to fifth hour after application (see Figs. 1,2, 3 and Fig. 7).

The oral administration of the combination of valerian root extract and lavender oil as a single dose led to extremely clear and statistically significant changes in 15 electrical brain activity of the test animals corresponding to those during sleep. This is particularly surprising, since the preparations were administered on the morning, i.e. after night sleep (inactive phase).

Example 1: Preparation of valerian root extract according to Ph. Eur.

Dried roots of Valeriana officinalis were extracted twice with the sevenfold 20 amount by weight of 70% (v/v) ethanol at 60°C for 1 h. The cooled mixture was filtrated. The filtrate was concentrated and dried at 60°C and 25 mbar for 8 h: 24% yield of dry extract.

Example 2: Preparation of lavender oil according to Ph. Eur.

Fresh flowers of Lavandula officinalis were subjected to steam distillation ac-25 cording to Ph. Eur. The essential oil thus obtained was further purified by distillation at max. 120°C and 10 to 20 mbar. -14-

Example 3: Combination preparation in form of a coated tablet

Table 2: Composition of coated tablets including 500 mg valerian root extract and 80 mg lavender oil

Item Ingredient Amount per tablet [mg] Amount per production scale for 30,000 tablets [kg] 1 valerian root extract 500.0 15.00 2 precipitated silica 100.0 3.00 3 lavender oil 80.0 2.40 4 microcrystalline cellulose 200.0 6.00 5 croscarmellose sodium 40.0 1.20 6 precipitated silica 20.0 0.60 7 magnesium stearate 5.0 0.15 8 hypromellose 40.0 1.20 9 Macrogol 1500 8.0 0.24 10 titanium dioxide E171 6.0 0.18 11 iron oxide yellow E172 3.0 0.09 12 talcum 3.0 0.09 1005.0 30.15 5 For production of a tablet including 500 mg of solid dry valerian root extract and 80 mg of liquid lavender oil, 15 kg of dry valerian root extract (item 1) were intensively mixed with 3 kg of precipitated silica (item 2). Subsequently, 2.4 kg of lavender oil (item 3) were added to this mixture, again followed by thorough mixing. A powdery mixture without liquid contents is obtained. In case the mix-10 ture of dry valerian root extract and lavender oil is prepared without precipitated silica, the lavender oil separates in liquid form and the mixture is not suitable for further processing into tablets. -15-

To the mixture of dry valerian root extract, silica and lavender oil, microcrystalline cellulose (excipient and binding agent; item 4), croscarmellose sodium (disintegrating accelerator, item 5), precipitated silica (flowing agent; item 6) are added and mixing is performed. Finally, magnesium stearate (lubricating agent; 5 item 7) is added and mixing is performed for another short period of 5 minutes.

Using a rotary tablet press, the resulting mixture is pressed into oval tablets having an individual mass of 945 mg. For preparation of a coating, the ingredients of the coating, i.e. hypromeliose (film-forming agent, item 8), Macrogol 1500 (softening agent, item 9), titanium dioxide and iron oxide (colouring pig-10 ments, items 10 and 11) as well as talcum (anti-sticking agent, item 12), are dispersed in water and coated on the tablets using a drum coater. As the product, uniformly coated yellow coloured film tablets including 500 mg dry valerian root extract and 80 mg lavender oil for oral administration are obtained.

Example 4: Combination preparation in form of a soft capsule 15 Table 3: Composition of mixture for filling of soft or hard capsules with 250 mg of dry valerian root extract and 40 mg of lavender oil

Item Ingredient Amount per capsule [mg] Amount per production scale for 100,000 capsules [kg] 1 hydrogenated fat 230.0 23.0 2 hydrogenated soybean oil 60.0 6.0 3 refined rapeseed oil 40.0 4.0 4 dry valerian root extract 250.0 25.0 5 lavender oil 40.0 4.0 620.0 62.0 -16-

For producing the composition for filling the capsules, hydrogenated fat (item 1), hydrogenated soybean oil (item 2) and refined rapeseed oil (item 3) are melted at 50°C or dissolved, respectively. The dry valerian root extract is homogeneously dispersed in the molten mass and, subsequently, the lavender oil is added 5 and homogeneously dispersed. The resulting composition for filling the capsules is stored in a tightly sealable temperable container under stirring and is filled into solid capsules at approx. 30-40°C, or is used for filling of soft capsules. The desired amount of 500 mg of dry valerian root extract and 80 mg of lavender oil can be applied orally by intake of two capsules. 10

Claims

1. Combination comprising a content of valerian root extract and lavender oil for use in treatment or prophylaxis of sleep disorders.

2. Combination for use according to claim 1, further comprising additives which are pharmaceutically acceptable or acceptable under food law.

3. Combination for use according to claim 1 or 2, wherein no further plant extract and/or plant oils and/or other pharmaceutically efficient ingredients (drugs) are contained.

4. Combination for use according to any one of claims 1 to 3, wherein the valerian root extract is prepared by extraction with aqueous ethanol or aqueous methanol.

5. Combination for use according to claim 4, wherein ethanol and water are used in extraction in a volume ratio of 30/70 to 90/10.

6. Combination for use according to claim 4, wherein methanol and water are used in extraction using a volume ratio of 40/60 to 55/45.

7. Combination for use according to any one of claims 1 to 6 wherein a dry valerian root extract is employed as the valerian root extract.

8. Combination for use according to claim 7, wherein the dry valerian root extract contains at least 0.25 wt.-% of sesquiterpene acids.

9. Combination for use according to claim 8, wherein the weight ratio of va-lernic acid to acetoxy valerenic acid in the dry valerian root extract is at least 2/1.

10. Combination for use according to any one of claims 1 to 9, wherein the lavender oil comprises 20.0 wt.-% to 45.0 wt.-% of linalool and 25.0 wt.-% to 47.0 wt.-% of linalyl acetate.

11. Combination for use according to claim 10, wherein the lavender oil additionally comprises at most 1.0 wt.~% limonene, at most 2.5 wt.-% 1,8-cineol, 0.1 wt.-% to 5.0 wt.-% 3-octanone, at most 1.2 wt.-% camphor, 0.1 wt.-% to 8.0 wt-% terpinen-4-ol, at least 0.2 wt.-% lavandulyl acetate, at least 0.1 wt.-% la-vandulol and at most 2.0 wt.-% alpha-terpineol.

12. Combination for use according to any one of claims 1 to 12, wherein 40 to 200 mg lavender oil and 80 to 600 mg valerian root extract per single dose are used.

13. Combination for use according to claim 12, wherein 40 to 80 mg of lavender oil and 250 to 500 mg of valerian root extract per single dose are used.

14. Combination for use according to any one of claims 1 to 13, wherein the administration occurs orally.

15. Combination for use according to any one of claims 1 to 14, wherein the sleep disorders are selected from disorders of initiating and maintaining sleep, circadian rhythm sleep disorders, sleep apnoea, nonorganic insomnia, nonor-ganic disorder of the circadian rhythm, sleepwalking (somnambulism), pavor nocturnus, as well as nightmares (anxiety dreams).

16. Combination preparation consisting of valerian root extract and lavender oil in a dosage form and, optionally, of additives which are pharmaceutically acceptable or acceptable under food law.